Psychopharmacology (1992) 109: 497-498
Psychopharmacology @~ S p r i n g e r - V e r l a g 1992
Concentration of ondansetron in cerebrospinal fluid following oral dosing in volunteers K.H. Simpson 1, P. Murphy 1, P.V. Colthup 2, and P. Whelan 3 1University Department of Anaesthesia and 3Department of Urology, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK 2Glaxo Group Research Ltd, Park Road, Ware, Hertfordshire SG12 ODP, UK Received April 3, 1992 / Final version June 5, 1992
Abstract. This s t u d y m e a s u r e d the c o n c e n t r a t i o n s of ond a n s e t r o n in p l a s m a a n d c e r e b r o s p i n a l fluid ( C S F ) in six volunteers after o r a l d o s i n g to s t e a d y state. O n d a n s e t r o n c o n c e n t r a t i o n s r a n g e d from 39.5-147 ng m l - 1 in p l a s m a a n d from 2.6-15.4 ng m1-1 in C S F . There was g o o d c o r r e l a t i o n between p l a s m a a n d C S F c o n c e n t r a t i o n s (r = 0.89, p = 0.017). C S F c o n c e n t r a t i o n s were less t h a n 15% of p l a s m a c o n c e n t r a t i o n s in all cases, i n d i c a t i n g t h a t the rate of p e n e t r a t i o n of the b l o o d b r a i n b a r r i e r b y o n d a n s e t r o n is low.
Key words:Ondansetron
Blood brain barrier- Cerebro-
spinal fluid
O n d a n s e t r o n is a highly p o t e n t a n d selective a n t a g o n i s t at the 5 - h y d r o x y t r y p t a m i n e - 3 ( 5 H T 3 ) receptor. It is an effective a n t i e m e t i c which is used in the t r e a t m e n t of n a u s e a a n d v o m i t i n g d u r i n g cancer c h e m o t h e r a p y ( H a i n s w o r t h et al. 1991). O n d a n s e t r o n is c u r r e n t l y being e v a l u a t e d in a n u m b e r of p s y c h i a t r i c indications. T h e range of activity of the d r u g suggests a site of a c t i o n at central n e r v o u s system 5 H T 3 receptors. This s t u d y was designed to d e t e r m i n e the c o n c e n t r a t i o n s of o n d a n s e t r o n in c e r e b r o s p i n a l fluid ( C S F ) in volunteers after oral d o s i n g to a s t e a d y state.
Prior to surgery each subject received five doses of 16 mg ondansetron (as two ondansetron hydrochloride dihydrate tablets each containing 8 mg of ondansetron base). The tablets were taken by mouth at 12 h intervals for 2 days prior to the day of surgery. The final dose was taken on the morning of surgery and the time noted. No premedication was given. Immediately prior to spinal anaesthesia 10 ml of venous blood was withdrawn for ondansetron measurement. Lumbar puncture was performed and 2 ml CSF was withdrawn for ondansetron assay. Immediately after the samples were withdrawn, following centrifugation, plasma and CSF were frozen at - 20°C until analysis. Plasma and CSF ondansetron concentrations were measured using high-performance liquid chromatography with ultraviolet detection (Colthup et al. 1991). The samples were assayed against calibration standards in the range 0-20 ng m l - 1 with 1.0 ng m l - 1 as the lowest standard and the limit of quantification when analyzing 1 ml of sample. When samples contained more than 20 ng m l - i ondansetron they were diluted to within the range of the assay. Prior to carrying out the analysis the plasma assay was shown to be valid for the analysis of CSF samples. Quality control samples (samples spiked with ondansetron base and stored at - 20°C) were used to show that the assay was satisfactory. Plasma and CSF concentrations were compared with reference to the time after the last dose of ondansetron for each volunteer. The ratio of ondansetron concentration in plasma and CSF was calculated in each case.
Results
Materials and methods Local Ethics Committee approval was granted for the study which involved six men undergoing elective urological surgery. All patients were scheduled to have lumbar puncture for the performance of spinal anaesthesia. Written consent was obtained from each patient prior to the start of the investigation. Only patients classified as 1, 2 or 3 using the American Anaesthetists Association Classification for preoperative state were included in the study. Patients with baseline laboratory investigations 10% above or below the normal range were excluded from the study. No restriction was placed upon concomitant therapy.
Correspondence to. K.H. Simpson
T h e m e a n (range) age of the p a t i e n t s was 67 (55-74) years. The m e a n (range) weight was 76 (65-80) k g a n d height was 172 (163-180) cm. Subject 3 missed the third a n d fifth dose of o n d a n s e t r o n b u t was still included in the analysis. T a b l e 1 shows the c o n c e n t r a t i o n s of o n d a n s e t r o n base in p l a s m a a n d C S F . T h e c o n c e n t r a t i o n s r a n g e d from 39.5-147 ng m1-1 in p l a s m a a n d 2.6 15.4 ng m1-1 in C S F . There was a c o r r e l a t i o n between p l a s m a a n d C S F o n d a n s e t r o n c o n c e n t r a t i o n s (r = 0.89, p = 0.017). The m e a n (range) C S F : p l a s m a o n d a n s e t r o n c o n c e n t r a t i o n ratio was 0.105 (0.054-0.149). T h e time after the final dose of o n d a n s e t r o n r a n g e d from 1.3 to 7.7 h. The lowest C S F : p l a s m a ratios were r e c o r d e d when samples were t a k e n less t h a n 1.5 h after the final dose of o n d a n s e t r o n .
498 Table 1. Concentrations of ondansetron in plasma and CSF Subject
Time after last dose (h)
Plasma CSF Ratio of conc. conc. CSF : plasma (ng ml- 1) (ng ml - 1) concs.
1. 2. 3.* 4. 5. 6.
3.5 1.3 7.7 1.4 2.5 1.3
147.0 93.6 39.5 48.2 56.2 66.9
15.4 8.0 5.9 2.6 8.4 5.9
0.105 0.085 0.t49 0.054 0.149 0.088
*This patient only received 3 doses of ondansetron
Discussion Three major factors influence the rate and extent to which drugs enter the brain and CSF: 1) the extent to which the drug is bound to proteins, 2) the degree of ionisation of the drug and 3) the lipid solubility of the non-ionised moiety. Ondansetron is bound to plasma protein to a moderate extent (70-76%) (Colthup and Palmer 1989) and to a greater extent in those disease states which result in elevated plasma protein concentrations. Thus the free drug concentration in equilibrium between the plasma and CSF compartments is approximately 25% of the total plasma concentration. Ondansetron has a p K a of 7.7 and therefore is only moderately ionised (67%) at blood pH. The logD (octanol/water) of ondansetron at p H 7.4 is 1.3 indicating that the drug is reasonably lipid soluble at physiological pH. The p H of blood and CSF, 7.4 and 7.3 respectively, would predict that at equilibrium the concentration of drug in each compartment would be similar.
In the present study the concentration of ondansetron in CSF was less than 15% of that in plasma. The lowest CSF : plasma concentrations were obtained when samples were taken less than 1.5 h after the final dose of ondansetron. As peak plasma concentrations of ondansetron occur 2-3 h after oral dosing, it is likely that at early time points insufficient time had elapsed for the drug to have equilibrated across the blood brain barrier. This study showed that ondansetron enters CSF in human volunteers after oral dosing to steady state and that plasma and CSF ondansetron concentrations correlated well. In all cases CSF concentrations were less than 15% of plasma concentrations compared to an expected equilibrium value of 25% if rapid penetration of the blood brain barrier occurred. This indicates that the rate of penetration of the blood brain barrier by ondansetron is low.
Acknowledgements. We wish to thank Dr. James Cornwall, Principal Research Scientist, Glaxo Group Research, for his support during the study.
References Colthup PV, Palmer JL (1989) The determination in plasma and pharmacokinetics of ondansetron. Eur J Cancer Clin Oncol 25 [Suppl 1] : $71-74 Colthup PV, Felgate CC, Palmer JL, Scully NL (1991) Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly. J Pharm Sci 80 [9] : 868-871 ttainsworth J, Harvey W, Pendergrass K, Kasimis B, Oblon D, Monoghan G, Gandara D, Hesketh P, Khojasten A, Harker G, York M, Siddique T, Finn A (1991) A single blind comparison of intravenous ondansetron a selective serotonin antagonist with intravenous metoclopramide in the prevention of nausea and vomiting associated with high dose cisplatin chemotherapy. J Clin Oncol 9 [5] : 721-728
Psychopharmacology @~ S p r i n g e r - V e r l a g 1992
Concentration of ondansetron in cerebrospinal fluid following oral dosing in volunteers K.H. Simpson 1, P. Murphy 1, P.V. Colthup 2, and P. Whelan 3 1University Department of Anaesthesia and 3Department of Urology, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK 2Glaxo Group Research Ltd, Park Road, Ware, Hertfordshire SG12 ODP, UK Received April 3, 1992 / Final version June 5, 1992
Abstract. This s t u d y m e a s u r e d the c o n c e n t r a t i o n s of ond a n s e t r o n in p l a s m a a n d c e r e b r o s p i n a l fluid ( C S F ) in six volunteers after o r a l d o s i n g to s t e a d y state. O n d a n s e t r o n c o n c e n t r a t i o n s r a n g e d from 39.5-147 ng m l - 1 in p l a s m a a n d from 2.6-15.4 ng m1-1 in C S F . There was g o o d c o r r e l a t i o n between p l a s m a a n d C S F c o n c e n t r a t i o n s (r = 0.89, p = 0.017). C S F c o n c e n t r a t i o n s were less t h a n 15% of p l a s m a c o n c e n t r a t i o n s in all cases, i n d i c a t i n g t h a t the rate of p e n e t r a t i o n of the b l o o d b r a i n b a r r i e r b y o n d a n s e t r o n is low.
Key words:Ondansetron
Blood brain barrier- Cerebro-
spinal fluid
O n d a n s e t r o n is a highly p o t e n t a n d selective a n t a g o n i s t at the 5 - h y d r o x y t r y p t a m i n e - 3 ( 5 H T 3 ) receptor. It is an effective a n t i e m e t i c which is used in the t r e a t m e n t of n a u s e a a n d v o m i t i n g d u r i n g cancer c h e m o t h e r a p y ( H a i n s w o r t h et al. 1991). O n d a n s e t r o n is c u r r e n t l y being e v a l u a t e d in a n u m b e r of p s y c h i a t r i c indications. T h e range of activity of the d r u g suggests a site of a c t i o n at central n e r v o u s system 5 H T 3 receptors. This s t u d y was designed to d e t e r m i n e the c o n c e n t r a t i o n s of o n d a n s e t r o n in c e r e b r o s p i n a l fluid ( C S F ) in volunteers after oral d o s i n g to a s t e a d y state.
Prior to surgery each subject received five doses of 16 mg ondansetron (as two ondansetron hydrochloride dihydrate tablets each containing 8 mg of ondansetron base). The tablets were taken by mouth at 12 h intervals for 2 days prior to the day of surgery. The final dose was taken on the morning of surgery and the time noted. No premedication was given. Immediately prior to spinal anaesthesia 10 ml of venous blood was withdrawn for ondansetron measurement. Lumbar puncture was performed and 2 ml CSF was withdrawn for ondansetron assay. Immediately after the samples were withdrawn, following centrifugation, plasma and CSF were frozen at - 20°C until analysis. Plasma and CSF ondansetron concentrations were measured using high-performance liquid chromatography with ultraviolet detection (Colthup et al. 1991). The samples were assayed against calibration standards in the range 0-20 ng m l - 1 with 1.0 ng m l - 1 as the lowest standard and the limit of quantification when analyzing 1 ml of sample. When samples contained more than 20 ng m l - i ondansetron they were diluted to within the range of the assay. Prior to carrying out the analysis the plasma assay was shown to be valid for the analysis of CSF samples. Quality control samples (samples spiked with ondansetron base and stored at - 20°C) were used to show that the assay was satisfactory. Plasma and CSF concentrations were compared with reference to the time after the last dose of ondansetron for each volunteer. The ratio of ondansetron concentration in plasma and CSF was calculated in each case.
Results
Materials and methods Local Ethics Committee approval was granted for the study which involved six men undergoing elective urological surgery. All patients were scheduled to have lumbar puncture for the performance of spinal anaesthesia. Written consent was obtained from each patient prior to the start of the investigation. Only patients classified as 1, 2 or 3 using the American Anaesthetists Association Classification for preoperative state were included in the study. Patients with baseline laboratory investigations 10% above or below the normal range were excluded from the study. No restriction was placed upon concomitant therapy.
Correspondence to. K.H. Simpson
T h e m e a n (range) age of the p a t i e n t s was 67 (55-74) years. The m e a n (range) weight was 76 (65-80) k g a n d height was 172 (163-180) cm. Subject 3 missed the third a n d fifth dose of o n d a n s e t r o n b u t was still included in the analysis. T a b l e 1 shows the c o n c e n t r a t i o n s of o n d a n s e t r o n base in p l a s m a a n d C S F . T h e c o n c e n t r a t i o n s r a n g e d from 39.5-147 ng m1-1 in p l a s m a a n d 2.6 15.4 ng m1-1 in C S F . There was a c o r r e l a t i o n between p l a s m a a n d C S F o n d a n s e t r o n c o n c e n t r a t i o n s (r = 0.89, p = 0.017). The m e a n (range) C S F : p l a s m a o n d a n s e t r o n c o n c e n t r a t i o n ratio was 0.105 (0.054-0.149). T h e time after the final dose of o n d a n s e t r o n r a n g e d from 1.3 to 7.7 h. The lowest C S F : p l a s m a ratios were r e c o r d e d when samples were t a k e n less t h a n 1.5 h after the final dose of o n d a n s e t r o n .
498 Table 1. Concentrations of ondansetron in plasma and CSF Subject
Time after last dose (h)
Plasma CSF Ratio of conc. conc. CSF : plasma (ng ml- 1) (ng ml - 1) concs.
1. 2. 3.* 4. 5. 6.
3.5 1.3 7.7 1.4 2.5 1.3
147.0 93.6 39.5 48.2 56.2 66.9
15.4 8.0 5.9 2.6 8.4 5.9
0.105 0.085 0.t49 0.054 0.149 0.088
*This patient only received 3 doses of ondansetron
Discussion Three major factors influence the rate and extent to which drugs enter the brain and CSF: 1) the extent to which the drug is bound to proteins, 2) the degree of ionisation of the drug and 3) the lipid solubility of the non-ionised moiety. Ondansetron is bound to plasma protein to a moderate extent (70-76%) (Colthup and Palmer 1989) and to a greater extent in those disease states which result in elevated plasma protein concentrations. Thus the free drug concentration in equilibrium between the plasma and CSF compartments is approximately 25% of the total plasma concentration. Ondansetron has a p K a of 7.7 and therefore is only moderately ionised (67%) at blood pH. The logD (octanol/water) of ondansetron at p H 7.4 is 1.3 indicating that the drug is reasonably lipid soluble at physiological pH. The p H of blood and CSF, 7.4 and 7.3 respectively, would predict that at equilibrium the concentration of drug in each compartment would be similar.
In the present study the concentration of ondansetron in CSF was less than 15% of that in plasma. The lowest CSF : plasma concentrations were obtained when samples were taken less than 1.5 h after the final dose of ondansetron. As peak plasma concentrations of ondansetron occur 2-3 h after oral dosing, it is likely that at early time points insufficient time had elapsed for the drug to have equilibrated across the blood brain barrier. This study showed that ondansetron enters CSF in human volunteers after oral dosing to steady state and that plasma and CSF ondansetron concentrations correlated well. In all cases CSF concentrations were less than 15% of plasma concentrations compared to an expected equilibrium value of 25% if rapid penetration of the blood brain barrier occurred. This indicates that the rate of penetration of the blood brain barrier by ondansetron is low.
Acknowledgements. We wish to thank Dr. James Cornwall, Principal Research Scientist, Glaxo Group Research, for his support during the study.
References Colthup PV, Palmer JL (1989) The determination in plasma and pharmacokinetics of ondansetron. Eur J Cancer Clin Oncol 25 [Suppl 1] : $71-74 Colthup PV, Felgate CC, Palmer JL, Scully NL (1991) Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly. J Pharm Sci 80 [9] : 868-871 ttainsworth J, Harvey W, Pendergrass K, Kasimis B, Oblon D, Monoghan G, Gandara D, Hesketh P, Khojasten A, Harker G, York M, Siddique T, Finn A (1991) A single blind comparison of intravenous ondansetron a selective serotonin antagonist with intravenous metoclopramide in the prevention of nausea and vomiting associated with high dose cisplatin chemotherapy. J Clin Oncol 9 [5] : 721-728
